Tumor-specific monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) have received little attention in central nervous system (CNS) malignancies, in part because the blood-brain barrier (BBB) and the neurovascular unit (NVU) create two compartments and limit brain delivery. Rituximab anti-CD20 mAb improves survival in a rat model of CNS B-cell lymphoma and in patients with primary CNS lymphoma (PCNSL), but trastuzumab anti-HER2 mAb has been ineffective in the treatment of breast cancer brain metastases. In this revised application we propose to evaluate mechanisms to enhance the delivery and efficacy of mAb-based therapies in two-compartment models of CNS tumors using permeability, tumor volumetrics and survival as end points. We will assess the permeability of rat brain tumor models using tumor-specific mAbs conjugated to ferumoxytol iron oxide nanoparticles, in comparison to dynamic contrast-enhanced magnetic resonance imaging of vasculature and quantitative autoradiography of drug delivery. We hypothesize that due to the long plasma half-life of therapeutic mAbs and their ability to bind to and accumulate at the target cancer cells, even a modest change in NVU function may impact delivery and efficacy of these agents. We will use osmotic BBB disruption to induce transient physical opening of the BBB. Targeting vascular endothelial growth factor with the antiangiogenic mAb bevacizumab paradoxically decreases vascular permeability while enhancing the efficacy of chemotherapy and mAbs. Targeting cell-cell adhesion and interactions with the extracellular matrix in the NVU with the anti-v integrin mAb intetumumab can increase tumor vascular permeability. Aim 1 is directed toward improving the efficacy of rituximab in a human B-cell CNS lymphoma model. We will image vascular permeability and test whether route of administration or vascular modification enhances the delivery and efficacy of rituximab with or without chemotherapy in intracerebral lymphoma xenografts. Additionally, we will evaluate the impact of rituximab on the seeding of B- cell lymphoma to the CNS from the periphery in a hematogenous model. In Aim 2 we will optimize the efficacy of trastuzumab and the ADC trastuzumab emtansine (T-DM1) in breast cancer intracerebral xenografts and hematogenous metastases. We will assess the effects of vascular targeting on vessel permeability, mAb delivery and T-DM1 efficacy. In Aim 3 we will develop and initiate an innovative trial of maintenance rituximab in PCNSL patients who achieve complete response after first-line and recurrent therapies, which will test mechanisms of recurrence. We will continue a Phase II trial of rituximab in conjunction with BBB disruption chemotherapy, and document and characterize neurocognitive function in PCNSL patients who have survived 2+ years in complete response after rituximab. This revised renewal will show the impact of transvascular delivery and the NVU in a rare primary brain tumor using mAb and drug conjugate approaches, and will extend and translate this approach to the more common problem of CNS breast cancer brain metastases.